Clearance Flashcards
What are the units for clearance?
Volume/time
Is clearance a constant? How do you know?
- Yes
- Because the formula involves K and Vd which are both constants
What is the formula for clearance using the compartment model?
Cl = K*Vd
Will each drug have their own characteristic clearance rate?
Yes
Which parts of ADME are involved in clearance?
Metabolism and excretion
What is the formula for clearance using the physiologic model?
Cl = Q*ER
- Q = blood flow
- ER = extraction ratio
What is the formula for clearance following model independent?
Cl = Do/AUC
What is the formula for ER (extraction ratio)?
(Ca-Cv) / Ca
What is the equation for renal clearance?
Clr = (Qu*Cu) / Cp
- Qu = rate of urine flow
- Cu = [drug] in urine
What can be concluded from the value of the clearance ratio? What is drug clearance compared to?
- Clearance ratio = drug clearance / inulin clearance
- Less than 1 = partially reabsorbed
- Equal to 1 = filtered only
- Greater than 1 = actively secreted
How can you determine renal clearance from a graph of dDu/dt (y axis) against Cp (x axis)?
Renal clearance will be the slope
What can be determined based on the slope of a plot on a graph of excretion rate (y axis) vs. Cp (x axis)?
- Perfectly linear slope (slope = 1) = filtration only (diffusion via concentration gradient; no protein)
- Slope greater than 1 = total excretion (transport protein present and filtration occurring at end)
- Slope less than 1 = active secretion (transport protein present, no filtration)
How can you calculate fraction of drug excreted (fe)? How can you calculate Clr from fe?
- fe = Du infinity / F*Do
- Clr = fe*Clt (total clearance)
What is the formula for clearance after IV infusion?
Cl = R / Css
- R = infusion rate
- Css = [drug] at steady state
How can you calculate t1/2 from Cl?
t1/2 = (0.693*Vd) / Cl
What affects hepatic clearance?
- Blood flow
- Intrinsic clearance
- Protein binding
What is the formula for hepatic clearance (Clh)?
Clh = [Q * (Ca-Cv)] / Ca = Q*ER
same as clearance using the physiologic model
What is Cl int? What is it used to describe?
- Intrinsic clearance
- Used to describe ability of the liver to remove drug in the absence of any flow limitation
- Reflects the inherent activity of the mixed-function oxidases
What extraction ratio makes a drug be considered highly extracted? What affects their clearance?
- Extraction ratio greater than 0.7 (70% extracted by the organ)
- This means the liver removes the drug almost as fast as its delivered to it
- Increase in blood flow will increase the hepatic clearance rate, so decrease in blood flow will decrease clearance rate
- These drugs are called blood flow limited/sensitive
What is important to note about drugs that affect cardiac output?
They will decrease organ blood flow, so will decrease their own clearance rate
What extraction ratio makes a drug be considered poorly extracted? What affects their clearance?
- Extraction ratio = 0.1-0.4
- These drugs are enzyme limited
- Hepatic clearance will increase if you induce the enzymes responsible for metabolizing the drugs; if you block these enzymes, hepatic clearance will decrease
- Same will occur if the drug is poorly extracted and eliminated via biliary excretion and you induce that component
What causes the majority of variability in half lives or clearance rates?
Drugs that are poorly extracted b/c px have different titers of hepatic enzymes
What is the effect on hepatic clearance if Q (blood flow) > intrinsic clearance?
Hepatic clearance = fu*Cl int (fraction unbound * intrinsic clearance; enzyme limited))
What is the effect on hepatic clearance if Q (blood flow) < intrinsic clearance?
Hepatic clearance = Q (blood flow limited)
